Methods and devices for activating brown adipose tissue with light

ABSTRACT

Methods and devices are provided for activating brown adipose tissue (BAT) with light. Generally, the methods and devices can activate BAT to increase thermogenesis, e.g., increase heat production in the patient, which over time can lead to weight loss and/or improved metabolic function. In one embodiment, a medical device is provided that activates BAT by using light to stimulate nerves that activate the BAT and/or to stimulate brown adipocytes directly, thereby increasing thermogenesis in the BAT and inducing weight loss and/or improved metabolic function through energy expenditure. The light can be configured to directly or indirectly stimulate the nerves and/or the brown adipocytes. The light can be configured to indirectly stimulate the nerves and/or the brown adipocytes by activating a light activatable medium administered to a patient and configured to respond to the light to cause activation of the brown adipose tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to International Application No. PCT/US11/66409 entitled “Methods And Devices For Activating Brown Adipose Tissue With Light” filed Dec. 21, 2011, and to U.S. Provisional Patent Application No. 61/428,008 entitled “Methods And Devices For Activating Brown Adipose Tissue With Light” filed Dec. 29, 2010, which are hereby incorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods and devices for inducing weight loss and/or improved metabolic function, and in particular to methods and devices for activating brown adipose tissue.

BACKGROUND OF THE INVENTION

Obesity is becoming a growing concern, particularly in the United States, as the number of people with obesity continues to increase and more is learned about the negative health effects of obesity. Severe obesity, in which a person is 100 pounds or more over ideal body weight, in particular poses significant risks for severe health problems. Accordingly, a great deal of attention is being focused on treating obese patients.

Surgical procedures to treat severe obesity have included various forms of gastric and intestinal bypasses (stomach stapling), biliopancreatic diversion, adjustable gastric banding, vertical banded gastroplasty, gastric plications, and sleeve gastrectomies (removal of all or a portion of the stomach). Such surgical procedures have increasingly been performed laparoscopically. Reduced postoperative recovery time, markedly decreased post-operative pain and wound infection, and improved cosmetic outcome are well established benefits of laparoscopic surgery, derived mainly from the ability of laparoscopic surgeons to perform an operation utilizing smaller incisions of the body cavity wall. However, such surgical procedures risk a variety of complications during surgery, pose undesirable post-operative consequences such as pain and cosmetic scarring, and often require lengthy periods of patient recovery. Patients with obesity thus rarely seek or accept surgical intervention, with only about 1% of patients with obesity being surgically treated for this disorder. Furthermore, even if successfully performed and initial weight loss occurs, surgical intervention to treat obesity may not result in lasting weight loss, thereby indicating a patient's need for additional, different obesity treatment.

Nonsurgical procedures for treating obesity have also been developed. However, effective therapies for increasing energy expenditure and/or altering a patient's metabolism, e.g., a basal metabolic rate, leading to improvements in metabolic outcomes, e.g., weight loss, have focused on pharmaceutical approaches, which have various technical and physiological limitations.

It has been recognized in, for example, U.S. Pat. No. 6,645,229 filed Dec. 20, 2000 and entitled “Slimming Device,” that brown adipose tissue (BAT) plays a role in the regulation of energy expenditure and that stimulating BAT can result in patient slimming. BAT activation is regulated by the sympathetic nervous system and other physiological, e.g., hormonal and metabolic, influences. When activated, BAT removes free fatty acids (FFA) and oxygen from the blood supply for the generation of heat. The oxidative phosphorylation cycle that occurs in the mitochondria of activated BAT is shown in FIGS. 1 and 2.

Accordingly, there is a need for improved methods and devices for treating obesity and in particular for activating BAT.

SUMMARY OF THE INVENTION

The present invention generally provides methods and devices for activating brown adipose tissue with light. In one embodiment, a medical method is provided that includes positioning a device in contact with tissue of a patient proximate to a depot of brown adipose tissue, and activating the device to deliver light energy to the patient to activate the brown adipose tissue and increase energy expenditure of the brown adipose tissue.

The light energy can have a variety of configurations. In one embodiment, the light energy can have a wavelength in an infrared range of about 0.7 to 1000 μm, e.g., in a range of about 0.7 to 5 μm. In another embodiment, the light energy can have a wavelength in an ultraviolet range of about 0.01 to 0.4 μm.

Optionally, a light activatable medium, e.g., a chemical such as at least one of a light dependent Beta-3 agonist and a light dependent form of norepinephrine, can be delivered to the depot of brown adipose tissue. The light activatable medium can be configured to respond to the light energy when the light energy is delivered to the patient, the response of the light activatable medium causing activation of the brown adipose tissue. The chemical can be configured to be active in the patient when the device is delivering the light energy to the patient, and can be configured to be inert in the patient when the device is not delivering the light energy to the patient. The device can be activated to deliver second light energy to the patient to cause the chemical to be inert in the patient. The light energy can have a different wavelength than the second light energy.

The light activatable medium can be delivered to the depot in any number of ways. For example, the light activatable medium can be delivered to the depot of brown adipose tissue by injecting the chemical into at least one of a circulatory system of the patient and a subcutaneous tissue of the patient, thereby allowing the chemical to circulate within the patient to the depot of brown adipose tissue. For another example, the light activatable medium can be delivered to the depot of brown adipose tissue by applying the chemical to an exterior surface of skin proximate to the depot of brown adipose tissue. For yet another example, the light activatable medium can be delivered to the depot of brown adipose tissue by alternating at least once between delivering the light activatable medium to the patient during a first period of time and not delivering the light activatable medium to the patient during a second period of time.

The depot of brown adipose tissue can have a variety of locations, such as being in a supraclavicular region of the patient.

In one embodiment, the device can be positioned in contact with tissue of the patient by transcutaneously applying the device to an exterior skin surface of the patient. In another embodiment, the device can be positioned in contact with tissue of the patient by subcutaneously positioning at least a portion of the device within the patient. Subcutaneously positioning the device in contact with tissue of the patient can include implanting the device entirely within the patient.

The light energy can be delivered to the patient in a variety of ways. In one embodiment, the light energy can be continuously delivered to the patient for a predetermined amount of time, e.g., at least four weeks. The device can be configured to be in continuous direct contact with the tissue of the patient for at least one day with the device continuously delivering the light energy to the patient for at least one day.

The method can include positioning a second device in contact with tissue of the patient proximate to another depot of brown adipose tissue, and activating the second device to deliver additional light energy to the patient to activate the other depot of brown adipose tissue and increase energy expenditure of the other depot of brown adipose tissue. The second device can deliver the additional light energy to the patient simultaneously with the device delivering the light energy to the patient.

The device can be activated in response to a trigger event including at least one of the patient eating, the patient resting, a threshold temperature of the patient, a directional orientation of the patient, a change in the patient's weight, a change in the patient's tissue impedance, manual activation by the patient or other human, a blood chemistry change in the patient, and a signal from a controller in electronic communication with the device.

The device is activated to deliver the light energy to the patient to activate the brown adipose tissue and/or and increase energy expenditure of the brown adipose tissue without cooling the patient or the brown adipose tissue and/or without any pharmaceutical being administered to the patient to activate the brown adipose tissue.

The device can have a variety of configurations. In one embodiment, the device can include a housing configured to be disposed in direct contact with the tissue of the patient proximate to the depot of brown adipose tissue, and a light source, e.g., a light emitting diode, a laser, etc., coupled to the housing and configured to deliver the light energy to the patient. The light source can be located within the housing. The housing can include a housing of a patch attached to the patient. The housing and the light source can be located outside a body of the patient, and a flexible cable can extend from the housing outside the body of the patient to a location inside the body of the patient proximate to the depot of brown adipose tissue. The flexible cable can be configured to deliver the light energy from the housing to the location inside the body.

The device can include a controller configured to turn the light source on to start the delivery of the light energy to the patient, turn the light source off to stop the delivery of the light energy to the patient, or both. The controller can be configured to be located remotely from the patient and to be in electronic communication with the light source. The controller can be configured to be implanted entirely within the patient.

The device can include a reservoir contained within the housing and storing a supply of a light activatable medium. The reservoir can be configured to deliver the light activatable medium to the depot of brown adipose tissue, and the light activatable medium can be configured to respond to the light energy when the light energy is delivered to the patient. The response of the light activatable medium can cause activation of the brown adipose tissue. The light activatable medium can be allowed to be delivered from the reservoir to the depot of brown adipose tissue during a first period of time, the light activatable medium can be prevented from being delivered from the reservoir to the depot of brown adipose tissue during a second period of time after the first time period, and the light activatable medium can be allowed to be delivered from the reservoir to the depot of brown adipose tissue during a third period of time after the second time period.

The method can have any number of variations. For example, the method can include targeting the light energy to a nerve innervating the brown adipose tissue to activate the brown adipose tissue. For another example, an intensity of the light energy can be reduced until a first predetermined threshold event occurs, and the intensity of the light energy can be subsequently increased until a second predetermined threshold event occurs. For yet another example, positioning a device in contact with tissue of a patient proximate to a depot of brown adipose tissue can include positioning the device proximate to at least one of a supraclavicular region, a nape of a neck, a scapula, a spinal cord, proximal branches of the sympathetic nervous system that terminate in BAT depots, and a kidney. For another example, the patient can be imaged to locate the depot of brown adipose tissue prior to positioning the device in contact with tissue of the patient proximate to the depot of brown adipose tissue.

For another example, the method can include removing the device from the patient, repositioning the device in contact with tissue of the patient proximate to another depot of brown adipose tissue, and activating the device to deliver additional light energy to the patient to activate the other depot of brown adipose tissue and increase energy expenditure of the other depot of brown adipose tissue. The depot of brown adipose tissue can be in a supraclavicular region on one of a left and right side of a sagittal plane of the patient, and the other depot of brown adipose tissue can be in a supraclavicular region on the other of the left and right side of the sagittal plane of the patient. The device can be removed and repositioned after the light energy has been delivered to the depot of brown adipose tissue for a threshold amount of time, e.g., at least seven days. The device can continuously deliver the light energy to the patient during the threshold amount of time. In response to a trigger event, the device can be removed from contact with tissue of the patient and repositioned to be in contact with another area of tissue of the patient proximate to another depot of brown adipose tissue. The trigger event can include at least one of the patient eating, the patient resting, a threshold temperature of the patient, a directional orientation of the patient, a change in the patient's weight, a change in the patient's tissue impedance, manual activation by the patient or other human, a blood chemistry change in the patient, and a signal from a controller in electronic communication with the device.

For yet another example, the method can include stopping application of the light energy, waiting a predetermined amount of time, and activating the device to deliver additional light energy to the patient to activate the depot of brown adipose tissue and increase energy expenditure of the brown adipose tissue. The stopping, the waiting, and the activating can be repeated until occurrence of a threshold event, e.g., at least one of a predetermined amount of time and a predetermined physiological effect.

In another embodiment, a medical method is provided that includes positioning a device in contact with tissue of a patient proximate to a first depot of brown adipose tissue, activating the device to deliver first light energy to the patient to activate the first depot and increase energy expenditure of the first depot, delivering the first light energy to the patient until a first threshold event occurs, when the first threshold event occurs, stopping delivery of the first light energy to the patient, delivering second light energy to the patient to activate a second depot of brown adipose tissue and increase energy expenditure of the second depot, delivering the second light energy to the patient until a second threshold event occurs, and, when the second threshold event occurs, stopping delivery of the second light energy.

The first and second light energies can have a variety of configurations. In one embodiment, the first light energy can have a wavelength in an infrared range of about 0.7 to 300 μm, e.g., in a range of about 0.7 to 5 μm, and the second light energy can have a wavelength in an infrared range of about 0.7 to 300 μm, e.g., in a range of about 0.7 to 5 μm. In another embodiment, the first light energy has a wavelength in an ultraviolet range of about 0.01 to 0.4 μm, and the second light energy has a wavelength in an ultraviolet range of about 0.01 to 0.4 μm. The first and second light energies can have identical wavelengths. In one embodiment, the first and second light energies can be simultaneously delivered to the patient. In another embodiment, the first and second energies can be sequentially delivered to the patient such that the patient receives only one of the first and second light energies at a time. When the second threshold event occurs, the device in contact with tissue of the patient proximate to the first depot can be activated to deliver third light energy to the patient to activate the first depot and increase energy expenditure of the first depot.

The first and second depots can have a variety of locations. In one embodiment, the first depot can be located on one of a left and right side of a sagittal plane of the patient, and the second depot can be located on the other of the left and right sides of the sagittal plane of the patient.

In one embodiment, the method can include delivering a light activatable medium, e.g., a chemical such as at least one of a light dependent Beta adrendergic agonist and a light dependent form of norepinephrine, to the first depot of brown adipose tissue. The light activatable medium can be configured to respond to the first light energy when the first light energy is delivered to the patient, the response of the light activatable medium causing activation of the first depot of the brown adipose tissue. Delivering the light activatable medium to the first depot of brown adipose tissue can include injecting the chemical into at least one of a circulatory system of the patient and a subcutaneous tissue of the patient, thereby allowing the chemical to circulate within the patient to the first depot of brown adipose tissue. Injecting the chemical into the at least one of the circulatory system of the patient and the subcutaneous tissue of the patient can allow the chemical to circulate within the patient to the second depot of brown adipose tissue. The chemical can be configured to respond to the second light energy when the second light energy is delivered to the patient, the response of the light activatable medium to the second light energy causing activation of the second depot of the brown adipose tissue. In one embodiment, the first and second light energies can be simultaneously delivered to the patient. In another embodiment, the first and second energies can be sequentially delivered to the patient such that the patient receives only one of the first and second light energies at a time. The chemical can be configured to be active in the patient when the device is activated and delivering the first light energy to the patient, and the chemical can be configured to be inert in the patient when the device is not activated and not delivering the first light energy to the patient.

In one embodiment, the first threshold event can include passage of a first predetermined amount of time, and the second threshold event can include passage of a second predetermined amount of time. In one embodiment, the first and second predetermined amounts of time can each be at least about 24 hours, e.g., at least about seven days.

The method can have any number of variations. For example, the method can include targeting the first light energy to a nerve innervating the first depot of the brown adipose tissue to activate the first depot of brown adipose tissue. For another example, before delivering the second light energy to the patient, the device can be repositioned to be in contact with tissue of the patient proximate to the second depot, and the device can be used to deliver the second light energy to the patient. For yet another example, a second device can be positioned in contact with tissue of the patient proximate to the second depot, and the second device can be used to deliver the second light energy to the patient.

In another embodiment, a medical method is provided that includes positioning a device on a body of a patient, generating light energy with the device, and targeting the light energy to stimulate a tissue that regulates energy expenditure within the patient. In one embodiment, the device can be positioned on skin of the patient. In another embodiment, at least a portion of the device can be positioned subcutaneously within the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

FIG. 1 is a schematic view of an oxidative phosphorylation cycle that occurs in mitochondria within BAT cells;

FIG. 2 is a schematic view of BAT mitochondria showing an oxidative phosphorylation cycle that occurs in the mitochondria;

FIG. 3 is a schematic view of PET-CT images showing the locations of BAT depots in a patient subject to a cold environment and in the patient in a normal, warm environment;

FIG. 4 is a transparent view of a portion of a human neck, chest, and shoulder area with a shaded supraclavicular region;

FIG. 5 is a graph showing voltage v. time for a generic light signal;

FIG. 6 is a front view of a body showing one embodiment of an electrical stimulation device positioned on opposite sides of the body's sagittal plane; and

FIG. 7 is a schematic view of one embodiment of a device for stimulating BAT.

DETAILED DESCRIPTION OF THE INVENTION

Certain exemplary embodiments will now be described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the devices and methods disclosed herein. One or more examples of these embodiments are illustrated in the accompanying drawings. Those skilled in the art will understand that the devices and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope of the present invention is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present invention.

Various exemplary methods and devices are provided for activating brown adipose tissue (BAT). In general, the methods and devices can activate BAT to increase thermogenesis, e.g., increase heat production and energy expenditure in the patient, which can treat metabolic disorders, such as obesity, diabetes, and hyperlipidemia. Therefore, activating BAT to increase thermogenesis can, over time, lead to one or more of weight loss, a change in the metabolism of the patient, e.g., increasing the patient's basal metabolic rate, and improvement of comorbidities in obese or non-obese patients, e.g., Type II diabetes, high blood pressure, etc. In an exemplary embodiment, a medical device is provided that activates BAT by using light to stimulate nerves that activate the BAT and/or to stimulate brown adipocytes directly, thereby increasing thermogenesis in the BAT and inducing weight loss and/or improving metabolic function through energy expenditure. As will be appreciated by a person skilled in the art, an obese patient can have a body mass index (BMI) greater than 30 kg/m², and a non-obese patient can have a BMI less than 30 kg/m². The light can be configured to directly or indirectly stimulate the nerves and/or the brown adipocytes. The light can be configured to indirectly stimulate the nerves and/or the brown adipocytes by activating a light activatable medium administered to a patient and configured to respond to the light to cause activation of the brown adipose tissue. In this way, weight loss and/or improved metabolic function can be induced without performing a major surgical procedure, without relying on cooling of the patient, and without surgically altering a patient's stomach and/or other digestive organs. Light is generally referred to herein as “light” or “light energy.”

Following a surgical procedure to treat obesity such as Roux-en-Y gastric bypass (RYGB), a patient can lose weight due to an increase in energy expenditure, as demonstrated in a rodent model for example in Stylopoulos et al., “Roux-en-Y Gastric Bypass Enhances Energy Expenditure And Extends Lifespan In Diet-Induced Obese Rats,” Obesity 17 (1 Oct. 2009), 1839-47. Additional data from Stylopoulos et al. (not published in the previous article or elsewhere as of the filing date of the present application) indicates that RYGB is also associated with increased levels of uncoupling protein 1 (UCP1), which is an uncoupling protein in mitochondria of BAT, as well as with a significant reduction in the size of fat stores within BAT and an increased volume of BAT. It thus appears that RYGB causes activation of BAT, although as discussed above, surgical procedures to treat obesity, such as gastric bypass, risk if not necessarily cause a variety of undesirable results. Devices and methods to activate BAT without a major surgical procedure like RYGB but instead with light stimulation to increase energy expenditure are therefore provided.

One characteristic of BAT that distinguishes it from white adipose tissue (WAT) stores is the high number of mitochondria in a single BAT cell. This characteristic makes BAT an excellent resource for burning energy. Another distinguishing characteristic of BAT is that when activated, UCP1 is utilized to introduce inefficiency into the process of adenosine triphosphate (ATP) creation that results in heat generation. Upregulation of UCP 1 is therefore a marker of BAT activation.

Activation of brown adipocytes leads to mobilization of fat stores within these cells themselves. It also increases transport of FFA into these cells from the extracellular space and bloodstream. FFAs in the blood are derived primarily from fats metabolized and released from adipocytes in WAT as well as from ingested fats. Stimulation of the sympathetic nervous system is a major means of physiologically activating BAT. Sympathetic nerve stimulation also induces lipolysis in WAT and release of FFA from WAT into the bloodstream to maintain FFA levels. In this way, sympathetic stimulation leads ultimately to the transfer of lipids from WAT to BAT followed by oxidation of these lipids as part of the heat generating capacity of BAT.

The controlled activation of BAT can be optimized, leading to weight loss and/or improved metabolic function, by reducing the stores of triglycerides in WAT. A person skilled in the art will appreciate that exposure to cold temperature leads to the activation of BAT to help regulate body temperature. This knowledge allows the location of BAT to be readily assessed using positron emission tomography-computed tomography (PET-CT) imaging. FIG. 3 shows scans of a patient subjected to a cold environment (left two images) and the same patient scanned in a normal, warm environment (right two images). Shown in black are regions of intense glucose uptake—namely, the brain, the heart, the bladder, and in the cold environment, BAT. However these images show the locations of BAT depots—namely the nape of the neck, the supraclavicular region, over the scapula, alongside the spinal cord, and around the kidneys as referenced by, for example, Rothwell et al, “A Role For Brown Adipose Tissue In Diet-Induced Thermogenesis,” Nature, Vol. 281, 6 Sep. 1979, and Virtanen et al., “Functional Brown Adipose Tissue in Healthy Adults,” The New England Journal of Medicine, Vol. 360, No. 15, Apr. 9, 2009, 1518-1525. Applying cold to BAT and/or otherwise activating BAT as discussed herein can thus improve glucose tolerance in a patient, and thereby be effective to treat a metabolic disease such as diabetes independent of weight loss and regardless of whether the patient is obese or non-obese. For example, in their paper, Bartelt et al., “Brown adipose tissue activity controls triglyceride clearance,” Nature Medicine, Vol. 17, Feb. 2011, 200-205, describe exposing mice to cold and detecting improved glucose tolerance after exposure to cold.

A person skilled in the art will appreciate that adult humans have substantial BAT depots, as indicated, for example, in J. M. Heaton, “The Distribution Of Brown Adipose Tissue In The Human,” J Anat., 1972 May, 112(Pt 1): 35-39, and W. D. van Marken Lichtenbelt et al, “Cold-Activated Brown Adipose Tissue in Healthy Men,” N. Engl. J. Med., 2009 April, 360, 1500-1508. A person skilled in the art will also appreciate that BAT is heavily innervated by the sympathetic nervous system, as indicated, for example, in Lever et al., “Demonstration Of A Catecholaminergic Innervation In Human Perirenal Brown Adipose Tissue At Various Ages In The Adult,” Anat Rec., 1986 July, 215(3): 251-5, 227-9. Further, “[t]he thin unmyelinated fibers that contain norepinephrine (and not NPY) are those that actually innervate the brown adipocytes themselves. They form a dense network within the tissue, being in contact with each brown adipocyte (bouton-en-passant), and their release of norepinephrine acutely stimulates heat production and chronically leads to brown adipose tissue recruitment”. B. Cannon, and J. Nedergaard, “Brown Adipose Tissue: Function And Physiological Significance,” Physiol Rev., 2004: 84: 277-359.

Nerves innervating BAT can be stimulated to activate UCP1 and hence increase energy expenditure through heat dissipation through transcutaneous and/or direct stimulation of nerves innervating BAT. Transcutaneous and direct stimulation are each discussed below in more detail.

In some embodiments, transcutaneous and/or direct stimulation of nerves innervating BAT can be combined with one or more treatments, before and/or after transcutaneous and/or direct stimulation of BAT, which can help encourage BAT stimulation and/or increase an amount of BAT in a patient. For non-limiting example, a pharmaceutical can be administered to a patient, the patient can be cooled, the patient can be heated, a magnetic field can be targeted to a region of a patient, a BAT-stimulation procedure can be performed on the patient directed to a BAT depot and/or to a nerve innervating BAT, the patient can engage in weight loss therapies, and/or a surgical procedure can be performed on the patient, such as a procedure to induce weight loss and/or to improve metabolic function, e.g., glucose homeostatis, lipid metabolism, immune function, inflammation/anti-inflammatory balance, etc. A non-limiting example of cooling the patient includes applying a cold pack to skin of the patient for a period of time. The cold pack can be applied to a region of the skin with a high concentration of cold receptors, such as near the wrists, ankles, and/or regions having thermosensitive transient receptor potential (TRP) channels (e.g., TRPA1, TRPV1, TRPM8, etc.). Alternatively or in addition, the cold pack can be applied to the skin proximate to a BAT depot and/or to nerves innervating a BAT depot. Providing electrical stimulation, e.g., using an implanted electrical stimulation device, such that the BAT depot can be simultaneously activated through a mechanism associated with a lowered body temperature and electrically stimulated, thereby potentially further encouraging additive or synergistic activation of the BAT. Exemplary embodiments of methods and devices for delivering an electrical signal to activate BAT are described in more detail in U.S. Pat. Pub. No. 2011/0270360 filed Dec. 29, 2010 entitled “Methods And Devices For Activating Brown Adipose Tissue Using Electrical Energy.” Non-limiting examples of a nerve stimulation technique configured to stimulate a nerve innervating BAT include delivery of a medium to the nerve that induces an action potential in the nerve, e.g., electricity, light, mechanical manipulation or vibration, a magnetic field, a chemical substance, etc. Non-limiting examples of a BAT-stimulation procedure include inducing differentiation of muscle, WAT, preadipocytes, or other cells to BAT, and/or implanting or transplanting BAT cells into a patient. Non-limiting examples of implanting or transplanting BAT cells include removing cells from a patient, culturing the removed cells, and reimplanting the cultured cells; transplanting cells from another patient; implanting cells grown from embryonic stem cells, adult stem cells, or other sources; and genetically, pharmacologically, or physically altering cells to improve cell function. Non-limiting examples of such weight loss therapies include a prescribed diet and prescribed exercise. Non-limiting examples of such a surgical procedure include gastric bypass, biliopancreatic diversion, vertical sleeve gastrectomy, adjustable gastric banding, vertical banded gastroplasty, intragastric balloon therapy, gastric plication, Magenstrasse and Mill, small bowel transposition, biliary diversion, vagal nerve stimulation, duodenal endoluminal barrier, and procedures that allow for removal of food from the stomach. Combining one or more treatments, particularly a weight loss therapy or a weight loss surgical procedure which does not activate BAT, e.g., a procedure other than RYGB, biliopancreatic diversion (BPD) with or without duodenal switch, or some duodenal or other intestinal barrier (e.g., a prescribed diet and/or exercise program, adjustable gastric banding, vertical banded gastroplasty, sleeve gastrectomy, gastric plication, Magenstrasse and Mill, intragastric balloon therapy, some duodenal or other intestinal barrier, small bowel transposition, and, with a means for acute or chronic activation of BAT such as the nerve stimulation discussed herein, can result in desirable patient outcomes through a combined approach.

Because BAT activation may lead to an increase in body temperature locally, regionally, or systemically, transcutaneous and/or direct stimulation of nerves innervating BAT can be combined with one or more heat dissipation treatments, before and/or after transcutaneous and/or direct stimulation of BAT. Non-limiting examples of such a heat dissipation treatment include inducing cutaneous/peripheral vasodilation, e.g., local or systemic administration of Alpha antagonists or blockers, direct thermal cooling, etc.

Whether BAT is activated directly and/or transcutaneously, target anatomical areas for BAT nerve stimulation and/or direct stimulation of brown adipocytes using light can include areas proximate to BAT depots, e.g., a supraclavicular region, the nape of the neck, over the scapula, alongside the spinal cord, near proximal branches of the sympathetic nervous system that terminate in BAT depots, and around at least one of the kidneys. Any BAT depot can be selected for activation. For non-limiting example, in one embodiment illustrated in FIG. 4, a device (not shown) can be positioned proximate to an area over a scapula in a supraclavicular region S. Identification of one or more BAT depots for activation can be determined on an individualized patient basis by locating BAT depots in a patient by imaging or scanning the patient using PET-CT imaging, tomography, thermography, or any other technique, as will be appreciated by a person skilled in the art. Non-radioactive based imaging techniques can be used to measure changes in blood flow associated with the activation of BAT within a depot. In one embodiment, a contrast media containing microbes can be used to locate BAT. The contrast media can be injected into a patient whose BAT has been activated. An energy source such as low frequency ultrasound can be applied to the region of interest to cause destruction of bubbles from the contrast media. The rate of refill of this space can be quantified. Increased rates of refill can be associated with active BAT depots. In another embodiment, a contrast media containing a fluorescent media can be used to locate BAT. The contrast media can be injected into a patient whose BAT has been activated. A needle based probe can be placed in the region of interest that is capable of counting the amount of fluorescent contrast that passes the probe. Increased counts per unit time correspond to increased blood flow and can be associated with activated BAT depots. Because humans can have a relatively small amount of BAT and because it can be difficult to predict where BAT is most prevalent even near a typical BAT depot such as the nape of the neck, imaging a patient to more accurately pinpoint BAT depots can allow more nerves innervating BAT to be stimulated and with greater precision. Any number of BAT depots identified through patient imaging can be marked for future reference using a permanent or temporary marker. As will be appreciated by a person skilled in the art, any type of marker can be used to mark a BAT depot, e.g., ink applied on and/or below the epidermis, a dye injection, etc. The marker can be configured to only be visible under special lighting conditions such as an ultraviolet light, e.g., a black light.

Methods of measuring BAT activation can be determined through energy expenditure involving continuous measurements of heat output (direct calorimetry) or inhaled/exhaled gas exchange (indirect calorimetry) in subjects. The term “energy expenditure,” as used herein, refers to the amount of energy (calories), that a person uses to breathe, circulate blood, digest food, support routine physiological functions and be physically active. To prevent weight gain, energy intake (caloric intake) must be balanced with energy expenditure.

Measurements of the heat released from a person's body can determine how much energy an activity has consumed. In addition, indirect calorimetry can measure oxygen consumption, carbon dioxide production and/or nitrogen excretion to calculate a ratio that reflects energy expenditure. A component of energy expenditure can be calculated as basal energy expenditure, which is the amount of energy required to maintain the body's normal metabolic activity, i.e. respiration, body temperature, etc.

Such energy expenditure or metabolic heat production in a subject can be assessed using several techniques. For measurement of the basal metabolic rate, the subject must be within its thermal neutral zone, which is the range of environmental temperatures across which the subject's body temperature can be maintained at its basal metabolic rate. The subject must be in a postabsorptive state, quiescent, in sexual repose, and resting but conscious. Since the latter prerequisite is often difficult to achieve with non-human subjects, the fasting heat production is used for animals which are quiet, but not necessarily resting.

Energy expenditure or metabolic heat production can be detected externally by a subject's heat loss pattern. Radiation, through which 40 to 60% of heat is lost from a subject, can be readily measured using any commercially available pyrometer or temperature sensor, since most radiated heat loss can be displayed in the 5-12 μm wavelength range of the electromagnetic spectrum. Direct and indirect calorimetry are further methods for assessing energy expenditure. Direct calorimetry measures heat loss from a subject directly by placing the subject at rest or exercising in a chamber surrounded by a waterjacket. Heat emitted from the subject raises the temperature of the water. The difference in the temperature of water entering and leaving the chamber reflects the subject's energy expenditure. Indirect calorimetry measures gas exchange and relates it to heat production. Indirect calorimetry involves monitoring of the amount of oxygen consumed (or conversely, the amount of carbon dioxide produced), and calculating the amount of energy expended by the subject, depending on the food substrate being utilized (e.g., fat, carbohydrate or protein).

Metabolic rate can also be measured through the use of doubly labeled water methods in which the average metabolic rate of an organism is measured over time. The use of doubly labeled water methods measures the subject's carbon dioxide production. Oxygen in body water can be lost in carbon dioxide, excretions and evaporative losses. However, hydrogen can only be lost through body water loss. Taking advantage of the change in body water and carbon dioxide production over time can be used to mathematically calculate metabolic rate.

Whether BAT is activated directly and/or transcutaneously, target cellular areas for BAT nerve stimulation and/or direct stimulation of brown adipocytes using light can include cell surface receptors (e.g., TGR5, β₁AR, β₂AR, β₃AR, etc.), nuclear receptors (e.g., PPARγ, FXR, RXR, etc.), transcription co-activators and co-repressors (e.g., PGC1α, etc.), intracellular molecules (e.g., 2-deiodinase, MAP kinase, etc.), UCP1 activators, individual cells and related components (e.g., cell surface, mitochondria, and organelles), transport proteins, etc.

In the course of treating a patient, BAT nerves and/or brown adipocytes can be stimulated at any one or more BAT depots directly or indirectly and can be stimulated simultaneously, e.g., two or more BAT depots being concurrently stimulated, or stimulated sequentially, e.g., different BAT depots being stimulated at different times. Simultaneous stimulation of BAT can help encourage more and/or faster energy expenditure. Sequential stimulation of BAT can help prevent the “burning out” of target nerves and can help stimulate the creation of new BAT cells. Sequential nerve stimulation can include stimulating the same BAT depot more than once, with at least one other BAT depot being activated before activating a previously activated BAT depot. Simultaneous and/or sequential stimulation can help prevent tachypylaxis.

The light energy, whether transcutaneously or directly delivered, can be configured in a variety of ways. In an exemplary embodiment, the light energy delivered to BAT can include light in an infrared range, e.g., having a wavelength in a range of about 0.7 to 1000 μm, such as in a near-infrared range of about 0.7 to 5 μm. In another exemplary embodiment, the light energy delivered to BAT can include light in an ultraviolet range, e.g., having a wavelength in a range of about 0.01 to 0.4 μm. In yet another exemplary embodiment, the light energy delivered to BAT can include light in a visible range, e.g., having a wavelength in a visible red range of about 620 to 750 nm. A time between start of light energy deliveries for light energy noncontinuously delivered to BAT can include can be of any regular, predictable duration, e.g., hourly, daily, coordinated around circadian, ultradian, or other cycles of interest, etc., such as about ten minutes, or can be of any irregular, unpredictable duration, e.g., in response to one or more predetermined trigger events, as discussed further below.

In one embodiment, the same light energy, e.g., light having the same wavelength, can be delivered to a particular BAT depot, either continuously or sequentially. In other words, light energy having a particular wavelength can be continuously delivered to a particular BAT depot, or light energy having a wavelength within a particular wavelength range, e.g., a near-infrared range, can be delivered to a particular BAT depot during a first period of time, delivery thereto can stop during a subsequent, second period of time, and then delivery thereto can begin again during a third period of time, etc. In another embodiment, a first light energy can be transcutaneously or directly delivered to a particular BAT depot, and then subsequently, either immediately thereafter or after a passage of a period of time, a second, different light energy can be delivered to the same particular BAT depot. In this way, chances of a BAT depot adapting to a particular light energy, e.g., to a particular wavelength of light, can be reduced, thereby helping to prevent the BAT depot from becoming less receptive to light stimulation.

A light source configured to deliver light energy can have any configuration. Generally, the light source can be configured to cause an action potential in a nerve. Exemplary embodiments of a light source include a laser, e.g., an ultraviolet laser source, and a light emitting diode (LED). Various exemplary embodiments of light sources configured to be delivered to a patient to stimulate a nerve are described in more detail in Herlitze et al., “New Optical Tools For Controlling Neuronal Activity,” Curr Opin Neurobiol. 2007 February; 17(1):87-94. (Epub 2006 Dec. 15), Wells et al., “Optically Medicated Nerve Stimulation: Identification Of Injury Thresholds,” Lasers Surg. Med. 2007 July, 39(6): 512-526, Wells et al., “Pulsed Laser Versus Electrical Energy For Peripheral Nerve Stimulation,” J. Neurosci. Methods 2007 Jul. 30, 163(2): 326-337 (Epub 2007 Mar. 31), Wells et al., “Biophysical Mechanisms Of Transient Optical Stimulation Of Peripheral Nerve,” Biophys. J. 2007 Oct. 1, 93(7): 2567-2580 (Epub 2007 May 25), Wells et al., “Application of Infrared Light For In Vivo Neural Stimulation,: J. Biomed. Opt. 2005 November-December, 10(6): 064003, and Wells et al., “Optical Stimulation Of Neural Tissue In Vivo,” Opt. Lett., 2005 Mar. 1, 30(5): 504-506.

In order to activate BAT using light, a sufficient burst of light energy is needed to cause an action potential. Such stimulation using light energy is similar to stimulating BAT using electrical energy to induce an action potential. As described in further detail in U.S. Pat. Pub. No. 2011/0270360 filed Dec. 29, 2010 entitled “Methods And Devices For Activating Brown Adipose Tissue Using Electrical Energy,” a modulating electrical signal delivered to BAT can include a pulse width, an amplitude/voltage, and a frequency. The amount of electrical energy to induce an action potential is related to the pulse width and the amplitude/voltage. Correspondingly, a light signal delivered to BAT can include a pulse width (generally corresponding to an electrical signal's pulse width), an intensity (generally corresponding to an electrical signal's amplitude/voltage), and a frequency (generally corresponding to an electrical signal's frequency). The amount of light energy to induce an action potential is related to the pulse width and the intensity. The amplitude/voltage required for an action potential for transcutaneously delivered electrical energy depends on properties of the tissue(s) to be penetrated by the electrical energy, resulting in an integrated tissue impedance. Similarly, the intensity required for an action potential for transcutaneously delivered light energy depends on the absorption and scattering coefficients of the tissue(s) to be penetrated by the light energy.

FIG. 5 illustrates amplitude/intensity, pulse width, activation signal pulse frequency, duration of signal train, and a time between start of signal trains for a generic (without any specified numerical parameters) light signal. In an exemplary embodiment, the light signal can have an intensity having an amplitude substantially equal to an electrical signal's voltage having an amplitude in a range of about 1 to 20 V, e.g., about 10 V, e.g., about 4 V, about 7 V, etc.; a pulse width in a range about 10 μs to 40 ms, e.g., about 0.1 ms, about 2 ms, about 20 ms, etc.; an activation signal pulse frequency in a range of about 0.1 to 40 Hz, e.g., about 6 Hz or in a range of about 1 to 20 Hz; and a duration of signal train in a range of about 1 second to continuous, e.g., about 30 seconds, etc. A time between start of signal trains for a noncontinuous light signal delivered to BAT can be of any regular, predictable duration, e.g., hourly, daily, coordinated around circadian, ultradian, or other cycles of interest, etc., such as about ten minutes or about ninety minutes, or can be of any irregular, unpredictable duration, e.g., in response to one or more predetermined trigger events, as discussed further below. Various exemplary embodiments of electrical signals that can be delivered to BAT and that can be correspondingly delivered to BAT using a light signal to result in substantially equal action potentials to that delivered by electrical signals are described in more detail in U.S. Pat. Pub. No. 2011/0270360 filed Dec. 29, 2010 entitled “Methods And Devices For Activating Brown Adipose Tissue Using Electrical Energy.” The intensity of a light signal delivered to a patient can ramp up until a predetermined event occurs, e.g., until the patient can feel it and/or until presence of activated BAT is detected.

The light source can be coupled to a power source configured to provide power to the light source, and can be coupled a controller configured to control various aspects of the light source, e.g., on/off status of the light source and adjustment of parameters such as wavelength, etc. The light source's light energy can be directed to a particular nerve or nerve bundle by being securely attached to a patient, e.g., using an adhesive, or otherwise maintained in a substantially constant relative positioned therewith. At least one sensor implanted within a patient or located external to a patient can be configured to sense one or more characteristics associated with the target, e.g., temperature, electrical signal, etc. The sensor can be configured to transmit sensed parameters to the controller. The controller can be configured to adjust the light source's output, e.g., pulse duration, power, duty cycle, frequency of delivery, wavelength, etc., based on one or more received sensed parameters, e.g., turn off the light source if a sensed temperature exceeds a predetermined threshold temperature.

The light source can be directed toward one or more particular nerves, e.g., sympathetic nerves innervating BAT, either directly or through one or more wave guides configured to deliver light energy, e.g., a flexible fiber optic cable. The one or more wave guides can be positioned to extend from the light source to a location remotely located therefrom, e.g., from a light source contained within a housing to a nerve bundle remotely located therefrom. In this way, a single housing including a plurality of light sources can be transcutaneously or subcutaneously applied to a patient and have a plurality of wave guides, each associated with one of the light sources, extending from the housing to a plurality of different targets. In an exemplary embodiment, a housing can have one or more wave guide coupled thereto, can be located external to a patient, and can include a laser generator contained therein. At least one laser emitter can be implanted within the patient, e.g., at a location proximate to a BAT depot. The one or more wave guides can extend between the laser generator and the laser emitter such that the laser generated by the laser generator can be carried by the one or more wave guides to the laser emitter, which can direct the generated laser to the BAT depot. In another embodiment, both a laser generator and a laser emitter in communication therewith can be located external to a patient's body. The external laser emitter can be configured to emit light that can safely pass through a surface of the patient's skin and any underlying tissue to reach a target, e.g., a nerve innervating BAT.

FIG. 7 illustrates one embodiment of a housing 100 configured to be transcutaneously or subcutaneously applied to a patient and including therein a light source 102, a light generator 104, a controller 106, a power source 108, and receiver circuitry 110 configured to interact with the controller 106. The receiver circuitry 110 is configured to receive data from a sensor device 112 that is configured to sense one or more characteristics associated with the patient, e.g., temperature, electrical signal, etc. The sensor device 112 is configured to transmit sensed parameters to the controller 106 via the receiver circuitry 110. The controller 106 is configured to adjust an output of the at least one light source 102, e.g., pulse duration, power, duty cycle, frequency of delivery, wavelength, etc., based on one or more received sensed parameters.

Whether a continuous light or an intermittent light is transcutaneously delivered, e.g., with a transdermal patch as discussed further below, or subcutaneously delivered via an at least partially implanted device, the light can be configured to activate BAT directly and/or configured to activate a light activation medium administered to the patient and configured to respond to the light energy when the light energy is delivered to the patient. In an exemplary embodiment, one light activation medium can be administered to a patient such that only one light activation medium is present in the patient's body, but any number of light activation mediums can be simultaneously or sequentially administered to a patient such that a plurality of light activation mediums are simultaneously present in the patient's body. The response of the light activatable medium can cause activation of the brown adipose tissue. The light activatable medium can have a variety of configurations. Generally, as mentioned above, the light activatable medium can be configured to respond to light energy delivered thereto to cause activation of brown adipose tissue. If two or more light activatable mediums are administered to a patient, each of the light activatable mediums can be configured to respond to a different light energy, e.g., to different wavelengths of light, which can help avoid “burning out” of a target, provide redundancy in case one source of light energy fails, and allow a BAT depot to be continuously stimulated while helping to avoid burn-out from a particular light wavelength or wavelength range. The light activatable medium can be administered to a patient prior to delivery of light energy thereto such that when the light energy is delivered to the patient, the light energy can activate the previously administered light activatable medium.

In an exemplary embodiment, the light activatable medium can include a chemical, e.g., a pharmaceutical or drug safe for patient administration such as a light dependent Beta-3 agonist, rhodopsin, or a light dependent form of norepinephrine. Various exemplary embodiments of chemicals configured to be activated by light, and various exemplary embodiments of light configured to activate such chemicals, are described in more detail in Lin et al, “Spatially Discrete, Light Driven Protein Expression,” Chemistry & Biology, Vol. 9, 1347-1353 (2002) and in Mayer et al., “Biologically Active Molecules With A Light Switch,” Angew. Chem. Int. Ed. 45, 4900-4921 (2006). Generally, a chemical administered to a patient can be configured to not appreciably bind with receptors in the patient until activated with a light having a particular wavelength or having a wavelength within a particular range. When the light reaches, e.g., contacts, the chemical in the patient, the chemical can be activated so as to stimulate BAT. The chemical can be configured to be activated by being exposed to a first light, e.g., a light having a first wavelength or being within a first wavelength range, and to be deactivated by being exposed to a second light, e.g., a light having a second, different wavelength or being within a second, different wavelength range. In an exemplary embodiment, the chemical can be activated by altering its configuration, e.g., changing from an inert molecule to a molecule with a binding affinity for one or more receptors, so as to bind with receptors on a brown adipocyte that can activate BAT. Although the chemical can be configured to be permanently changed, the chemical can be configured to be deactivated with a second, different light such that the molecule with a binding affinity changes back to the inert molecule. A chemical configured to be permanently changed can allow for spatial specificity, e.g., for a chemical to be delivered a particular target in the body, such as with a topically applied cream. A chemical configured to be intermittently changed can allow for spatial and/or temporal specificity. In another embodiment, the chemical can be activated by releasing molecules with a binding affinity for one or more receptors. In still another embodiment, the chemical can have one or more light emitting genes attached thereto. The one or more light emitting genes can be configured to be activated when exposed to light having a particular wavelength or having a wavelength in a particular range. Various exemplary embodiments of light emitting genes are described in more detail in U.S. Pat. Pub. No. 2009/0081715 filed Sep. 5, 2008 entitled “Engineered Light-Emitting Reporter Genes.”

The chemical can be administered to a patient in any number of ways, as will be appreciated by a person skilled in the art. In one embodiment, a light activatable medium chemical can be administered to a patient by injecting the chemical into the patient, e.g., using a needle. The light activatable medium can be injected at any one or more locations, e.g., directly into a BAT depot, into a patient's circulatory system, subcutaneous tissue, etc. A particular depth of a needle can be selected to help ensure that the chemical is injected into a desired target. By injecting the chemical into a circulatory system of the patient, the chemical can be administered to the patient at any one or more selected body locations and can be allowed to circulate within the patient. In this way, regardless of where light is delivered to a patient, e.g., targeted to a shoulder area, targeted to a wrist area, etc., the light can be configured to activate the chemical that has circulated throughout the patient, including to the area being targeted by the light. In another embodiment, a light activatable medium chemical can be administered to a patient by topically applying the chemical to an exterior surface of a patient's skin, such as by applying a gel or cream thereto. The chemical can be topically applied at any location on a patient's body, but in an exemplary embodiment, the chemical can be topically applied at a skin surface proximate to a BAT depot. Similar to that discussed above regarding an injected light activatable medium chemical, a topically applied light activatable medium chemical can be configured to circulate within the patient. In still another embodiment, a light activatable medium chemical can be administered to a patient by administering a pill containing the chemical to the patient. The pill can be administered to the patient in any way, e.g., swallowing, as will be appreciated by a person skilled in the art. In an exemplary embodiment, the pill can be delivered to a patient's gut, e.g., stomach and/or intestine, which can target antagonists to CB-1 receptors that reside within the gut and that lead to activation of BAT. Various exemplary embodiments of controlling drug delivery to a targeted region of the body using a pill are described in more detail in U.S. patent application Ser. No. 12/976,648 filed Dec. 22, 2010 entitled “Pill Catchers” and in U.S. Pat. Pub. No. 2009/0018594 filed Oct. 4, 2007 entitled “Methods And Devices For Medical Treatment.” In yet another embodiment, a light activatable medium chemical can be administered to a patient through inhalation.

A light activatable medium can be delivered to a patient continuously or intermittently. In an exemplary embodiment, a light activatable medium can be intermittently delivered to a patient by alternating at least once between delivering the light activatable medium to the patient during a first period of time and not delivering the light activatable medium to the patient during a second period of time. One exemplary embodiment of a continuous delivery includes a time-release pill, microsphere, patch, etc. configured to constantly release relatively small doses of a light activatable medium into the patient. One exemplary embodiment of an intermittent delivery includes a time-release pill configured to alternately release a light activatable medium during a first period of time and not release the light activatable medium during a second period of time. The light activatable medium can be released on any time schedule, e.g., a particular amount or volume released for one hour every two hours for a total of four one-hour releases. Another exemplary embodiment of an intermittent delivery includes a pump, e.g., an infusion pump, configured to sporadically release a light activatable medium contained in a reservoir. The light activatable medium can be released on a regular schedule, e.g., released for ten seconds every ten minutes, or on an irregular schedule, e.g., in response to a predetermined trigger event or whenever the pump is manually activated. The reservoir can be refillable and/or replaceable. In one embodiment, the reservoir can be refillable by removing reservoir from the patient, adding an amount of light activatable medium to the reservoir, and reattaching or reimplanting the reservoir. In another embodiment, the reservoir can be configured to be refillable when implanted within a patient, such as by using a needle inserted through the patient's skin, through a needle-penetrable, self-sealing septum extending across the reservoir, and into the reservoir, as will be appreciated by a person skilled in the art. The pump and/or the reservoir in communication therewith can be implanted or transdermal. In one embodiment, a reservoir storing a supply of a light activatable medium, e.g., a liquid drug, can be contained within a housing. The housing can be configured to be implanted within a patient or to be located external to a patient, such as by being applied to an external skin surface of the patient such as with an adhesively-attached patch. Whether implanted within a patient or not, the reservoir can have an elongate delivery tube such as a catheter coupled thereto such that the light activatable medium contained with the reservoir can be released into the catheter and flow through the catheter to a location remote from the reservoir. Various exemplary embodiments of pumps and reservoirs configured to deliver a fluid to a patient are described in more detail in U.S. Pat. Pub. No. 2009/0204131 filed Feb. 12, 2008 entitled “Automatically Adjusting Band System With MEMS Pump” and U.S. Pat. Pub. No. 2009/0171375 filed Dec. 27, 2007 entitled “Controlling Pressure In Adjustable Restriction Devices.” Another exemplary embodiment of an intermittent delivery includes periodic injections of a light activatable medium into a patient. The injections can occur on a regular schedule, e.g., once every week, or irregularly, e.g., when a predetermined trigger event such as eating occurs.

Light energy delivered to a BAT depot can be applied continuously, in predetermined intervals, in sporadic or random intervals, in response to one or more predetermined trigger events, or in any combination thereof. If the light is continuously delivered to the patient, particular care should be taken to ensure that the light delivered to the patient will not damage the target nerves or tissues. For light energy delivered intermittently, nerve or tissue damage can be reduced, if not entirely prevented, by selecting an on/off ratio in which the light is “off” for more time than it is “on.” For non-limiting example, light energy can be delivered to BAT intermittently with an on/off ratio of about 1:19, e.g., light energy delivered for 30 seconds every ten minutes (30 seconds on/9.5 minutes off). The device delivering the light can be configured to respond to one or more predetermined trigger events, e.g., events that are sensed by or otherwise signaled to the device. Non-limiting examples of trigger events include the patient eating, the patient resting (e.g., sleeping), a threshold temperature of the patient (e.g., a temperature in the stimulated BAT depot or a core temperature), a directional orientation of the patient (e.g., recumbent as common when sleeping), a change in the patient's weight, a change in the patient's tissue impedance, manual activation by the patient or other human (e.g., via an onboard controller, via a wired or wirelessly connected controller, or upon skin contact), a blood chemistry change in the patient (e.g., a hormonal change), low energy expenditure, menstrual cycles in women, medication intake (e.g., an appetite suppressant such as topiramate, fenfluramine, etc.), a nutrient change in the patient (e.g., a change in glucose, amino acids, free fatty acids, and their metabolites, etc.), and a manually-generated or automatically-generated signal from a controller in electronic communication, wired and/or wireless, with the device. Non-limiting examples of nutrients include lipids such as bile acids, cholesterol and its metabolites, aliphatic fatty acids, peptides and proteins, etc. In one embodiment, the patient eating can be determined through a detection of heart rate variability, as discussed in more detail in U.S. patent application Ser. No. 12/980,695 filed Dec. 29, 2010 and entitled “Obesity Therapy And Heart Rate Variability” and U.S. patent application Ser. No. 12/980,710 filed Dec. 29, 2010 and entitled “Obesity Therapy And Heart Rate Variability.” The controller can be internal to the device, be located external from but locally to device, or be located external and remotely from device. As will be appreciated by a person skilled in the art, the controller can be coupled to the device in any way, e.g., hard-wired thereto, in wireless electronic communication therewith, etc. In some embodiments, multiple devices can be applied a patient, and at least two of those devices can be configured to deliver light energy based on different individual trigger events or combinations of trigger events.

Generally, transcutaneous stimulation of BAT can include applying a device to an exterior skin surface of a patient proximate to a BAT depot and activating the device to deliver light energy to the BAT depot. In this way, the light energy can activate the BAT proximate to the device by stimulating the nerves innervating the BAT and/or by stimulating brown adipocytes directly. As mentioned above, two or more transcutaneous devices, same or different from one another, can be simultaneously applied to a patient, proximate to the same BAT depot or to different BAT depots. Although a patient can have two or more transcutaneously applied devices and although the devices can be configured to simultaneously deliver light energy to BAT, the devices can be configured such that only one delivers light energy at a time. As also mentioned above, a transcutaneous device can be rotated to different BAT depots of a patient and deliver light energy to each of the BAT depots. Rotating a device between two or more different locations on a patient's body and/or removing a device from a patient when not in use can help prevent nerve or tissue desensitization and/or dysfunction, can help reduce any adverse effects of a device's attachment to the body, e.g., irritation from an adhesive applying a device to skin, and/or can help stimulate creation or replication of new BAT in multiple locations on a patient's body. For non-limiting example, the device can be placed in varying positions on the body to modulate the activity of different regions of BAT. In one embodiment, the device can be worn on one side of the neck, e.g., the left side, for a period of time and then on an opposite side of the neck, e.g., the right side, for the next time period, etc. In another embodiment, the device can be worn on an anterior side of a BAT depot, e.g., front of a left shoulder on one side of the patient's coronal plane, for a period of time and then on an opposite, posterior side of the BAT depot, e.g., back of the left shoulder on the opposite side of the patient's coronal plane, for the next period of time. In yet another embodiment, illustrated in FIG. 6, a device 10 can be worn proximate to a BAT depot on one of a left and right side of a sagittal plane P in a supraclavicular region of a body 12 for a period of time and then the device 10 can be worn on the other of the left and right sides of the sagittal plane P in the supraclavicular region proximate to another BAT depot for the next period of time. Although the same device 10 is shown in FIG. 6 as being sequentially relocated to different tissue surface or skin positions on the body 12, as discussed herein, one or both of the devices can be implanted and/or two separate devices can be used with a patient such that a first device is positioned at one location and a second device is positioned at a second, different location.

The transcutaneous device used to transcutaneously activate BAT can have a variety of sizes, shapes, and configurations. Generally, the device can be configured to provide and/or deliver light energy to tissue at predetermined intervals, in response to a manual trigger by the patient or other human, in response to a predetermined trigger event, or any combination thereof.

Various exemplary embodiments of transcutaneous devices configured to stimulate nerves are described in more detail in U.S. Patent Publication No. 2009/0132018 filed Nov. 16, 2007 and entitled “Nerve Stimulation Patches And Methods For Stimulating Selected Nerves,” U.S. Patent Publication No. 2008/0147146 filed Dec. 19, 2006 and entitled “Electrode Patch And Method For Neurostimulation,” U.S. Patent Publication No. 2005/0277998 filed Jun. 7, 2005 and entitled “System And Method For Nerve Stimulation,” U.S. Patent Publication No. 2006/0195153 filed Jan. 31, 2006 and entitled “System And Method For Selectively Stimulating Different Body Parts,” U.S. Patent Publication No. 2007/0185541 filed Aug. 2, 2006 and entitled “Conductive Mesh For Neurostimulation,” U.S. Patent Publication No. 2006/0195146 filed Jan. 31, 2006 and entitled “System And Method For Selectively Stimulating Different Body Parts,” U.S. Patent Publication No. 2008/0132962 filed Dec. 1, 2006 and entitled “System And Method For Affecting Gastric Functions,” U.S. Patent Publication No. 2008/0147146 filed Dec. 19, 2006 and entitled “Electrode Patch And Method For Neurostimulation,” U.S. Patent Publication No. 2009/0157149 filed Dec. 14, 2007 and entitled “Dermatome Stimulation Devices And Methods,” U.S. Patent Publication No. 2009/0149918 filed Dec. 6, 2007 and entitled “Implantable Antenna,” U.S. Patent Publication No. 2009/0132018 filed Nov. 16, 2007 and entitled “Nerve Stimulation Patches And Methods For Stimulating Selected Nerves,” U.S. patent application Ser. No. 12/317,193 filed Dec. 19, 2008 and entitled “Optimizing The Stimulus Current In A Surface Based Stimulation Device,” U.S. patent application Ser. No. 12/317,194 filed Dec. 19, 2008 and entitled “Optimizing Stimulation Therapy Of An External Stimulating Device Based On Firing Of Action Potential In Target Nerve,” U.S. patent application Ser. No. 12/407,840 filed Mar. 20, 2009 and entitled “Self-Locating, Multiple Application, And Multiple Location Medical Patch Systems And Methods Therefor,” U.S. patent application Ser. No. 12/605,409 filed Oct. 26, 2009 and entitled “Offset Electrodes.”

In an exemplary embodiment, the transcutaneous device can include a light energy stimulation patch configured to be applied to an external skin surface and to deliver light energy to tissue below the skin surface, e.g., to underlying BAT. The light energy can be delivered any depth below the skin surface, such as up to about 2 cm below the skin surface, e.g., at a maximum penetration depth in a range of about 1 to 2 cm. The patch can be configured to generate or provide its own light energy with a light source or light generator and/or to deliver light energy received by the patch from a source in communication with the patch. The device can be wireless and be powered by an on-board and/or external source, e.g., inductive power transmission. The patch can be attached to the skin in any way, as will be appreciated by a person skilled in the art. Non-limiting examples of patch application include using a skin adhesive locally (e.g., on patch rim), using a skin adhesive globally (e.g., on skin-contacting surfaces of the patch), using an overlying support (e.g., gauze with taped edges), using an adherent frame allowing interchangeability (e.g., a brace or an article of clothing), being subdermally placed with wireless connectivity (e.g., Bluetooth) or a transdermal light source, and using any combination thereof. The device can include receiver circuitry configured to interact with a controller in electronic communication with an on-board light source of the device such that the controller can control at least some functions of the light source, e.g., on/off status of the light source and adjustment of parameters such as wavelength, etc. In an exemplary embodiment, a light energy stimulation patch can include a plurality of LEDs, each of which can be the same as or different from any one or more of the other LEDs. The LEDs can each be configured to emit light that can safely pass through a surface of the patient's skin and any underlying tissue to reach a target, e.g., a nerve innervating BAT.

In use, and as mentioned above, a light stimulation patch can be worn continuously or intermittently as needed. The patch can be placed proximate to a BAT depot, such as over the left supraclavicular region of the patient's back, for a predetermined amount of time, e.g., twelve hours, one day, less than one week, seven days (one week), one month (four weeks), etc., and can continuously deliver a light to the BAT. As mentioned above, the BAT depot can be identified by imaging the patient prior to application of the patch proximate to the BAT depot. Seven days is likely the longest period an adhesive can be made to stick to the skin of a patient without modification and can thus be a preferable predetermined amount of time for patches applied to skin with an adhesive. After the predetermined amount of time, the patch can be removed by a medical professional or the patient, and the same patch, or more preferably a new patch, can be placed, e.g., on the right supraclavicular region of the patient's back for another predetermined amount of time, which can be the same as or different from the predetermined amount of time as the first patch applied to the patient. This process can be repeated for the duration of the treatment, which can be days, weeks, months, or years. In some embodiments, the process can be repeated until occurrence of at least one threshold event, e.g., a predetermined amount of time, a predetermined physiological effect such as a predetermined amount of weight lost by the patient, etc. If the same patch is relocated from a first region, e.g., the left supraclavicular region, to a second region, right supraclavicular region, the patch can be reconditioned after removal from the first region and prior to placement at the second region. Reconditioning can include any one or more actions, as will be appreciated by a person skilled in the art, such as replacing one or more patch components, e.g., a battery, an adhesive, etc.; cleaning the patch; etc.

Optionally, a patch or other transdermal device can be attached to a patient using a placement tool. Generally, the placement tool can facilitate consistent placement of the device on the patient's skin proximate to a targeted area, e.g., a BAT depot. In one embodiment, the placement tool can be aligned with a bony landmark of the patient, e.g., connecting medial and lateral heads of clavicle and/or acromion of the scapula, such that after alignment thereto, the targeted area can be repeatedly consistently identified via the placement tool. Bony landmarks can be identified in any way, such as by imaging the patient prior to application of the device, as discussed above. The placement tool can be a standalone instrument, or it can be built into the device, e.g., the device including one or more grid marks, numbers, letters, or other measurement markings.

To more accurately simulate a weight loss surgery and/or invasive metabolic disorder treatment that has a continuous or chronic effect on a patient for an extended period of time, the patch can be placed on a patient and continuously or chronically deliver light energy thereto for an extended, and preferably predetermined, amount of time. In an exemplary embodiment, the predetermined amount of time can be at least four weeks. The light energy can be delivered to same BAT depot for the predetermined amount of time, or two or more different BAT depots can be stimulated throughout the predetermined amount of time, e.g., left and right supraclavicular regions being stimulated for alternate periods of seven days to total one month of predetermined time. Continued or chronic nerve stimulation to activate BAT can increase BAT energy expenditure over time and potentially induce more or faster weight loss and/or metabolism change than periodic or intermittent nerve stimulation. The light energy can be the same or can vary, e.g., vary by being delivered at different wavelengths, during the amount of time such that the light energy is continuously and chronically applied to the patient to provide 24/7 treatment mimicking the 24/7 consequences of surgery. The continuous amount of time the patient is stimulated with light can be a total amount of continuous activation of any one BAT depot (e.g., activation of a single BAT depot), sequential activation of two or more BAT depots, simultaneous activation of two or more BAT depots, or any combination thereof. A total amount of time of sequential activation of different BAT depots can be considered as one extended amount of time despite different areas of BAT activation because activation of one BAT depot may cause the brain to signal for BAT activation in other BAT depots.

Generally, direct activation of BAT can include implanting a device below the skin surface proximate to a BAT depot, e.g., within a BAT depot, and activating the device to deliver light energy to the nerves innervating the BAT depot and/or to brown adipocytes directly. BAT itself is densely innervated, with each brown adipocyte being associated with its own nerve ending, which suggests that stimulating the BAT directly can target many if not all brown adipocytes and depolarize the nerves, leading to activation of BAT. The sympathetic nerves that innervate BAT can be accessed directly through standard surgical techniques, as will be appreciated by a person skilled in the art. The device can be implanted on a nerve or placed at or near a nerve cell's body or perikaryon, dendrites, telodendria, synapse, on myelin shelth, node of Ranvier, nucleus of Schwann, or other glial cell to stimulate the nerve. While implanting such a device can require a surgical procedure, such implantation is typically relatively short, outpatient, and with greatly reduced risks from longer and more complicated surgical procedures such as gastric bypass. In an exemplary embodiment, a stimulation device with at least one light source can be at least partially implanted in the patient, and more preferably entirely within the patient. A person skilled in the art will appreciate that any number of light sources, e.g., one or more, can be at least partially implanted in the patient. The light source can be implanted in a location sufficiently close to the nerves innervating the BAT so that when activated, the light energy emitted by the light source is sufficiently transferred to adjacent nerves, causing these nerves to depolarize. As mentioned above, the device can include receiver circuitry configured to interact with a controller in electronic communication with the light source such that the controller can control at least some functions of the light source, e.g., on/off status of the light source, switching between multiple light sources included in the device, and adjustment of parameters such as wavelength, etc.

Various exemplary embodiments of devices configured to directly apply a signal to stimulate nerves are described in more detail in U.S. Patent Publication No. 2005/0177067 filed Jan. 26, 2005 and entitled “System And Method For Urodynamic Evaluation Utilizing Micro-Electronic Mechanical System,” U.S. Patent Publication No. 2008/0139875 filed Dec. 7, 2006 and entitled “System And Method For Urodynamic Evaluation Utilizing Micro Electro-Mechanical System Technology,” U.S. Patent Publication No. 2009/0093858 filed Oct. 3, 2007 and entitled “Implantable Pulse Generators And Methods For Selective Nerve Stimulation,” U.S. Patent Publication No. 2010/0249677 filed Mar. 26, 2010 and entitled “Piezoelectric Stimulation Device,” U.S. Patent Publication No. 2005/0288740 filed Jun. 24, 2004 and entitled, “Low Frequency Transcutaneous Telemetry To Implanted Medical Device,” U.S. Pat. No. 7,599,743 filed Jun. 24, 2004 and entitled “Low Frequency Transcutaneous Energy Transfer To Implanted Medical Device,” U.S. Pat. No. 7,599,744 filed Jun. 24, 2004 and entitled “Transcutaneous Energy Transfer Primary Coil With A High Aspect Ferrite Core,” U.S. Pat. No. 7,191,007 filed Jun. 24, 2004 and entitled “Spatially Decoupled Twin Secondary Coils For Optimizing Transcutaneous Energy Transfer (TET) Power Transfer Characteristics,” and European Patent Publication No. 377695 published as International Patent Publication No. WO1989011701 published Nov. 30, 2004 and entitled “Interrogation And Remote Control Device.”

In use, at least one light source of an implantable stimulation device can be placed in the area of a BAT depot. The light source can be in electronic communication with a device external to the patient's skin to adjust characteristics such as wavelength, turn it on and off, etc. The external device can be positioned near the patient's skin, e.g., using a belt, a necklace, a shirt or other clothing item, furniture or furnishings such as a chair or a pillow, or can be a distance away from the patient's skin, such as a source located elsewhere in the same room or the same building as the patient. The light stimulation device can include circuitry configured to control an activation distance, e.g., how close to a power source the light stimulation device must be to be powered on and/or begin delivering light energy. Correspondingly, the external device can include a transmitter configured to transmit a signal to the light stimulation device's circuitry. If implanted, the device can include an internal power source, e.g., a battery, a capacitor, stimulating electrodes, a kinetic energy source such as magnets positioned within wired coils configured to generate energy within the coils when shaken or otherwise moved, etc. In one embodiment, a battery can include a flexible battery, such as a Flexion battery available from Solicore, Inc. of Lakeland, Fla. In another embodiment, a battery can include an injectable nanomaterial battery. The power source can be configured to be recharged by transcutaneous means, e.g., through transcutaneous energy transfer (TET) or inductive coupling coil, and/or can be configured to provide power for an extended period of time, e.g., months or years, regardless of how long the power source is intended to provide power to the device. In some embodiments, a power source can be configured to provide power for less than an extended period of time, e.g., about 7 days, such as if a battery is replaceable or rechargeable and/or if device real estate can be conserved using a smaller, lower power battery.

The controller, and/or any other portion of the device or external device, as will be appreciated by a person skilled in the art, can be configured to measure and record one or more physical signals relating to the activation of BAT. For non-limiting example, the physical signals can include voltage, current, impedance, temperature, time, moisture, salinity, pH, concentration of hormones or other chemicals, etc. The recorded physical signals can be presented to the patient's physician for evaluation of system performance and efficacy of brown adipose activation. Also, the recorded physical signals can be used in a closed-loop feedback configuration to allow the device, e.g., the controller, to dynamically adjust the light energy settings used for treatment.

The devices disclosed herein can be designed to be disposed of after a single use, or they can be designed to be used multiple times. In either case, however, the device can be reconditioned for reuse after at least one use. Reconditioning can include any combination of the steps of disassembly of the device, followed by cleaning or replacement of particular pieces, and subsequent reassembly. In particular, the device can be disassembled, and any number of the particular pieces or parts of the device can be selectively replaced or removed in any combination. Upon cleaning and/or replacement of particular parts, the device can be reassembled for subsequent use either at a reconditioning facility, or by a surgical team immediately prior to a surgical procedure. Those skilled in the art will appreciate that reconditioning of a device can utilize a variety of techniques for disassembly, cleaning/replacement, and reassembly. Use of such techniques, and the resulting reconditioned device, are all within the scope of the present application.

Preferably, the invention described herein will be processed before use. First, a new or used instrument is obtained and if necessary cleaned. The instrument can then be sterilized. In one sterilization technique, the instrument is placed in a closed and sealed container, such as a plastic or TYVEK bag. The container and instrument are then placed in a field of radiation that can penetrate the container, such as gamma radiation, x-rays, or high-energy electrons. The radiation kills bacteria on the instrument and in the container. The sterilized instrument can then be stored in the sterile container. The sealed container keeps the instrument sterile until it is opened in the medical facility.

It is preferred that device is sterilized. This can be done by any number of ways known to those skilled in the art including beta or gamma radiation, ethylene oxide, steam, and a liquid bath (e.g., cold soak). An exemplary embodiment of sterilizing a device including internal circuitry is described in more detail in U.S. Patent Publication No. 2009/0202387 filed Feb. 8, 2008 and entitled “System And Method Of Sterilizing An Implantable Medical Device.”

One skilled in the art will appreciate further features and advantages of the invention based on the above-described embodiments. Accordingly, the invention is notto be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety. 

What is claimed is:
 1. A medical method, comprising: positioning a housing in contact with tissue of a patient, the housing having housed therein a light source operatively positioned proximate to a depot of brown adipose tissue; activating the light source to deliver light energy to the patient to activate the brown adipose tissue and increase energy expenditure of the brown adipose tissue; after the activating, sensing with a sensor a characteristic of the brown adipose tissue and transmitting the sensed characteristic to a controller operatively coupled to the light source; changing, with the controller, the light energy being delivered by the light source based on the sensed characteristic, wherein the changing includes either turning off the light source to stop delivering the light energy or altering at least one of pulse duration, power, duty cycle, frequency of delivery, and wavelength of the light energy; delivering a light activatable medium to the depot of brown adipose tissue, the light activatable medium being configured to respond to the light energy when the light energy is delivered to the patient, the response of the light activatable medium causing activation of the brown adipose tissue; and delivering a different light activatable medium to the depot of brown adipose tissue, wherein: the housing has an additional light source housed therein positioned proximate to the depot of brown adipose tissue; the method further comprises activating the additional light source to deliver additional light energy to the patient to activate the brown adipose tissue and increase energy expenditure of the brown adipose tissue; the light energy has a first wavelength and the additional light energy has a different wavelength; the light activatable medium is activated by the first wavelength but is not activatable by the different wavelength; and the different light activatable medium is activated by the different wavelength but is not activatable by the first wavelength.
 2. The method of claim 1, wherein the first wavelength of the light energy is in an infrared range of about 0.7 to 1000 μm.
 3. The method of claim 1, wherein the first wavelength of the light energy is in an ultraviolet range of about 0.01 to 0.4 μm.
 4. The method of claim 1, wherein delivering the light activatable medium to the depot of brown adipose tissue comprises alternating at least once between delivering the light activatable medium to the patient during a first period of time and not delivering the light activatable medium to the patient during a second period of time.
 5. The method of claim 1, further comprising targeting the light energy to a nerve innervating the brown adipose tissue to activate the brown adipose tissue.
 6. The method of claim 1, wherein the depot of brown adipose tissue is in a supraclavicular region of the patient.
 7. The method of claim 1, wherein positioning the housing in contact with tissue of the patient comprises transcutaneously applying the housing to an exterior skin surface of the patient.
 8. The method of claim 1, wherein positioning the housing in contact with tissue of the patient comprises subcutaneously positioning at least a portion of the housing within the patient.
 9. The method of claim 1, wherein the light energy delivered by the light source is continuously delivered to the patient for a predetermined amount of time in a range of one day to four weeks.
 10. The method of claim 9, further comprising after the light energy has been continuously delivered to the patient for the predetermined amount of time, removing the housing from the patient; repositioning the housing in contact with tissue of the patient with the light source proximate to another depot of brown adipose tissue; and activating the light source to deliver additional light energy by the light source to the patient to activate the other depot of brown adipose tissue and increase energy expenditure of the other depot of brown adipose tissue.
 11. The method of claim 10, wherein the depot of brown adipose tissue is in a supraclavicular region on one of a left and right side of a sagittal plane of the patient, and the other depot of brown adipose tissue is in a supraclavicular region on the other of the left and right side of the sagittal plane of the patient.
 12. The method of claim 10, further comprising, after the additional light energy has been delivered to the patient, in response to a trigger event, removing the housing from contact with tissue of the patient proximate to the other depot of brown adipose tissue and repositioning the housing to be in contact with another area of tissue of the patient with the light source proximate to a third depot of brown adipose tissue, wherein the trigger event includes at least one of the patient eating, the patient resting, a threshold temperature of the patient, a directional orientation of the patient, a change in the patient's weight, a change in the patient's tissue impedance, manual activation by the patient or other human, and a blood chemistry change in the patient.
 13. The method of claim 9, wherein the predetermined amount of time is at least seven days.
 14. The method of claim 9, further comprising waiting a second predetermined amount of time after the light source has delivered the light energy to the patient and then activating the light source to deliver additional light energy to the patient to activate the depot of brown adipose tissue and increase energy expenditure of the brown adipose tissue.
 15. The method of claim 1, wherein the characteristic of the depot of brown adipose tissue includes at least one of temperature and an electrical signal. 